Premium
Quantitative methylation analysis reveals gender and age differences in p16 INK 4a hypermethylation in hepatitis B virus‐related hepatocellular carcinoma
Author(s) -
Wang Yongfeng,
Cheng Jin,
Xu Chunhui,
Liu Shuang,
Jiang Suzhen,
Xu Qiang,
Chen Xiangmei,
Zhuang Hui,
Lu Fengmin
Publication year - 2012
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2011.02696.x
Subject(s) - p14arf , dna methylation , hepatocellular carcinoma , methylation , hepatitis b virus , biology , cancer research , medicine , pathology , virus , gene , tumor suppressor gene , carcinogenesis , gene expression , immunology , genetics
Background Frequent promoter hypermethylation of the inhibitors in either Rb or p53 pathways is associated with the hepatocellular carcinoma ( HCC ) development. Objective To quantitatively assess the gradual changes of the promoter methylation of p14 ARF , p15 INK 4b, p16 INK 4a and CCND 2 genes in hepatitis B virus ( HBV ) infection‐related HCC . Methods A total of 118 pairs of tumour and their corresponding non‐tumour tissues were collected from HCC patients with evidence of HBV infection. The promoter methylation status was analysed by combined DNA methylation‐sensitive and methylation‐dependent restriction endonuclease digestion, followed by subsequential quantitative PCR assay. Results Promoter hypermethylation frequencies were gradually increased from 6.25% in normal liver tissues to 21.19% in adjacent non‐tumour and to 40.68% in tumour tissues for p16 INK 4a ( P = 0.000), and from none to 10.20% and to 29.59% for CCND 2 ( P = 0.001). The hypermethylation intensities in HCC tissues were also significantly increased ( P = 0.0018 for p16 INK 4a, P = 0.0001 for CCND 2). Altogether, 48.93% cases were found with increased hypermethylation intensity of either p16 INK 4a and/or CCND 2 promoter in tumour tissues, compared with their matched non‐tumour tissues. In addition, tumour tissue p16 INK 4a promoter hypermethylation was significantly higher in male than that in female gender patients in frequency ( P = 0.041) and was significantly increased in patients older than 50 years of age in intensity ( P = 0.0021). No hypermethylation of p14 ARF or p15 INK 4b was found. Conclusion Our study demonstrated that from normal liver to the adjacent cirrhotic liver and to the HCC tissues, p16 INK 4a hypermethylation was gradually increased both in frequency and in intensity, such increase might be gender and age related.